1. Field of the Invention
The invention relates generally to non-irritating, non-toxic compositions providing enhanced bioavailability and more specifically to alkyl glycoside or saccharide alkyl ester compositions for delivery of therapeutic agents to a subject, including methods and compositions to modulate the pregastric absorption of drugs administered to the oral cavity.
2. Background Information
Therapeutic agents are often combined with various surfactants. Yet, surfactants are frequently irritating to the skin and other tissues, including mucosal membranes such as those found in the nose, mouth, eye, vagina, rectum, esophagus, intestinal tract, and the like. Many surfactants also cause proteins to denature, thus destroying their biological activity. Another serious limitation to the development and use of such agents is the ability to deliver them safely, non-invasively, efficiently and stably to the site of action. Therefore, an ideal enhancing surfactant will stabilize the therapeutic agent, be non-toxic and non-irritable to the skin or mucosal surfaces, have antibacterial activity, and enhance the passage or absorption of the therapeutic agent through various membrane barriers without damaging the structural integrity and biological function of the membrane and increase bioavailability of the agent.
A number of formulation approaches to producing rapidly disintegrating or so-called “fast-dispersing” dosage forms have been described previously. Upon disintegration in the oral cavity, the drug substance is swallowed resulting in pregastric absorption and ultimately gastric absorption. The term “pre-gastric absorption” is commonly used to refer to the absorption of the active ingredient into that part of the alimentary canal prior to the stomach and includes buccal, sublingual, oropharyngeal and oesophageal absorption. The term “gastric absorption” is commonly used to refer to the absorption of the active ingredient in the stomach and intestines. Varying amounts of drug may be absorbed as drug passes through the pregastric portion of the alimentary canal. However, the bulk of the drug passes into the stomach and is absorbed in the usual gastric absorption mode in which enteric dosage forms such as tablets, capsules, or liquids are absorbed. As drug is absorbed from the intestines, the drug is brought directly into the liver, where, depending upon its specific chemical structure, it may be metabolized and eliminated by enzymes that perform the normal detoxifying processes in liver cells. This elimination is referred to as “first-pass” metabolism or the “first-pass” effect in the liver. The resulting metabolites, most often substantially or completely inactive compared to the original drug, are often found circulating in the blood stream and subsequently eliminated in the urine and/or feces. Formulation approaches to producing rapidly disintegrating or rapidly dispersing dosage forms are provided in US Patent Application No. 2006/0134194, incorporated herein by reference.
Previously described fast-disperse dosage forms provide for the dosage form to disintegrate or dissolve when placed in the mouth in order to promote pre-gastric or gastric absorption of the active ingredient, however the fast dispersing dosage forms of the present invention provide improved characteristics, such as speeding the onset of drug action and reducing the first-pass effect drug metabolism.